The long range objective of this project is to understand fundamental mechanisms of ventilatory control, particularly mechanisms controlling ventilation during mild or moderate physical activity. In this project period, neural mechanisms causing short and long term modulation of the exercise ventilatory response will be investigated. Short term modulation causes immediate (within trial) changes in the exercise ventilatory response whereas long term modulation changes system properties and responses over a time span of several to many trials. Awake goats, trained to exercise on a treadmill, will be used as an experimental model. There are four primary aims. First, the hypothesis will be tested that short term modulation with increased respiratory dead space requires changes in spinal respiratory neuron excitability via serotonergic mechanisms. Goats with subarachnoid catheters in the thoracic spinal cord will be used to determine if pharmacological blockade of spinal serotonin receptors prevents short term modulation. Second, the hypothesis will be tested that repeated, paired chemoreceptor stimulation and exercise alter future ventilatory responses to exercise alone (ie. long term modulation). In normal goats, repeated presentations of exercise with hypoxia, increased dead space or inspired helium/oxygen mixtures will alter normal chemoreceptor feedback during exercise for 20-30 trials on four days. Long term modulation would be indicated by augmented (hypoxia, dead space) or attenuated (helium/oxygen) ventilatory responses during subsequent exercise trials. Third, the effects of thoracic dorsal rhizotomy (TDR) on selected spinal neurotransmitters (5-HT, TRH, Substance P and CGRP) will be investigated using immunocytochemical techniques. We propose to determine if changes observed during the previous project period result from TDR per se, or if they are associated with compensatory mechanisms underlying recovery of ventilatory function with repeated exercise trials. Finally, electromyographic analysis of respiratory muscle activation will be used to determine if TDR diminishes respiratory muscle activation or disrupts coordination between inspiratory and expiratory muscles, thereby accounting for ventilatory failure during initial exercise trials following TDR. Changes in muscle utilization will be observed during functional recovery, a form of long term modulation. Short and long term modulation of the exercise ventilatory response indicate that the system adapts to changing conditions (eg. pregnancy, onset of pulmonary disease, etc.). An understanding of these mechanisms may provide insight into normal compensatory processes, and the rationale for therapeutic intervention during disease. The results of these studies also have implications in the design and interpretation of many studies on ventilatory control, since this is a control system commonly assumed to be inflexible or "hard wired".